Camptothecin (CPT)-derived drugs, such as irinotecan (CPT-11), are typically used for treating solid brain, colon, and lung tumors, as well as for treating refractory forms of leukemia and lymphoma. See Pommier Nat. Rev. Cancer, 6(10):789 802.
The antineoplastic efficacy of CPT-11 is limited by a delayed diarrhea that occurs about 2 to 4 days after administration. Severe diarrhea induced by CPT-11 and other camptothecin-derived drugs has significant negative medical consequences, especially for the elderly. The onset of diarrhea necessitates a reduction in CPT-11 dosage or even a complete halt of therapy until the patient's intestinal function returns to normal.
The mechanism of CPT-11-induced diarrhea has been the subject of intensive study. CPT-11, which is a prodrug, is hydrolyzed by carboxylesterases in the liver to its therapeutically active form, 7-ethyl-10 hydroxycamptothecin (SN-38). SN-38 undergoes further metabolism in both the liver and intestines, where it is conjugated with glucuronic acid to form the inactive compound, SN-38G. CPT-11, SN-38, and SN-38G are then eliminated via the gastrointestinal tract in bile.
The highly expressed carboxylesterase (CES) 2 in the intestine effectively converts CPT-11 to SN-38 with a potency 100-fold higher than its liver homolog, CES1. The conversion results in a high local concentration of toxic SN-38 in the intestinal lumen, causing damage to intestinal epithelial cells and subsequent diarrhea.
Several compounds have been recently identified that show a high selectivity for inhibiting CES2 as compared to CES1. See Stoddard et al. 2010, J. Pest. Sci., 35(3):240-249; Hatfield et al. 2011, Expert Opin. Ther. Pat., 21(8):1159-117). However, these compounds have low solubility and poor pharmaceutical properties.
There is a need to identify improved selective CES2 inhibitors that can ameliorate diarrhea induced by CPT-11 administered for treating cancer.